1. Field of the Invention
This invention relates to pharmaceutical gallium compositions, particularly those having enhanced oral bioavailability relative to simple gallium salts and methods for their use. Gallium has demonstrated pharmaceutical value for the treatment of many human and animal disorders, including hypercalcemia, cancer, and especially certain widespread degenerative or metabolic bone diseases such as osteoporosis and Paget's disease.
2. References
The following references are cited in this application as superscript numbers at the relevant portion of the application:
1. Hart and Adamson, Proceedings of the National Academy of Sciences, U.S.A., 68:1623-1626 (1971) PA0 2. Collery, U.S. Pat. No. 4,596,710 PA0 3. Adamson et al., Chemotherapy Reports, 59:599-610 (1975) PA0 4. Warrell, Jr. et al., U.S. Pat. No. 4,529,593 PA0 5. Bockman et al., U.S. Pat. No. 4,704,277 PA0 6. Warrell, Jr. et al., "Gallium in the Treatment of Hypercalcemia and Bone Metastasis", in "Important Advances in Oncology 1989", DeVita, Jr., Editor, J.P. Lippincott Company, Philadelphia, Pa. PA0 7. Porter, "The Use of Opadry, Coateric, and Surelease in the Aqueous Film Coating of Pharmaceutical Oral Dosage Forms", at pp. 317-362 of "Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms", McGinity, Editor, Marcel Decker, Inc., New York, N.Y. (1989) PA0 8. Nagai et al., "Applications of HPMC and HPMCAS Aqueous Film Coatings of Pharmaceutical Dosage Forms", at pp. 81-152 of "Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms", McGinity, Editor, Marcel Decker, Inc., New York, N.Y. (1989) PA0 9. Jones, "Production of Enteric Coated Capsules", Manufacturing Chemist & Aerosol News, 41:43-57 (1970) PA0 10. Messora, U.S. Pat. No. 3,927,195 PA0 11. Porter, "Coating of Pharmaceutical Dosage Forms", at Chapter 91, pp. 1633-1643, of "Remington's Pharmaceutical Sciences", Gennaro et al., Editors, 17th Ed. (1985) PA0 12. Windholz et al., The Merck Index, 9th Edition, pp. 741-742, Merck & Company, Rahway, N.J. (1976) PA0 13. Foster et al., "Gallium Nitrate: The Second Metal With Clinical Activity", Cancer Treatment Reports, 70:1311-1319 (1986) PA0 14. Hider et al., U.S. Pat. No. 4,575,502 PA0 15. Finnegan et al., Inorganic Chemistry, 26:2171-2176 (1987) PA0 16. Farrar et al., Food and Chemical Toxicology, 26:523-525 (1988) PA0 17. Ott, International Journal of Artifical Organs, 6:173-175 (1983)
The disclosures of each of these references are incorporated herein by reference in their entirety.
3. State of the Art
Gallium is known to accumulate in certain tumors, inflamed tissue, and bone tissue by mechanisms that are largely unknown. Binding of gallium to transferring, particularly lactoferrin, is thought to be responsible for some of the transport of gallium in the body, and for the concentration of gallium in certain tumors and inflamed tissues. Radioactive .sup.67 Ga citrate compositions are used in patients to diagnose certain malignancies and infections, including those in bone tissue. Non-radioactive gallium compositions, and compositions containing other Group IIIa elements, have been found effective in treating some tumors in animals and humans. Gallium is thought to be the most effective of these Group IIIa elements.sup.1,3,4. The art recognizes that gallium is useful for the treatment and prevention of many human and other mammalian diseases, including hypercalcemia, cancer, and certain degenerative or metabolic bone diseases such as osteoporosis and Paget's disease.sup.2-6,13. Gallium itself appears to be the active agent; the form in which the gallium is administered (e.g. as the nitrate, sulfate, or chloride) does not appear to affect its activity to any significant extent.sup.3,6.
Gallium is particularly useful in the treatment and prevention of hypercalcemia and certain bone diseases. Treatable bone diseases include such widespread conditions as osteoporosis, osteopenia, Paget's disease, malignant bone disease, bone degeneration due to hyperparathyroidism, and other conditions associated with increased bone resorption or turnover in humans or animals.sup.4,6. In addition to the above, it has been found that gallium increases calcium accretion in bone and decreases bone resorption.sup.5.
Specifically, Warrell et al..sup.4,6 and Bockman et al..sup.5 disclose treatments using gallium salts, preferably gallium nitrate, for regulating the resorption of calcium from bone in certain bone diseases and hypercalcemia, and for increasing the mass and tensile strength of bone. Warrell et al..sup.4 discloses that such regulation entails the generation of plasma gallium concentrations in the patient of from about 0.9 to 2.0 .mu.g/ml whereas Bockman et al..sup.5 recite the generation of plasma gallium concentrations in the patient of from about 0.1 to 5.0 .mu.g/ml.
Treatment of cancer with gallium nitrate is disclosed in Foster et al..sup.13 which teaches the administration (by infusion) of gallium nitrate at 700-750 mg/m.sup.2 by short infusion every 2-3 weeks; 300 mg/m.sup.2 /day by short infusion for three consecutive days, to be repeated every 2 weeks; and 300 mg/m.sup.2 /day by continuous infusion for 7 consecutive days, to be repeated every 3-5 weeks. Specific cancers treated in this reference include, by way of example, refractory lymphomas, small cell lung carcinoma, genitourinary malignancies (renal, bladder, prostate, testicular), and multiple myeloma.
On the other hand, Collery.sup.2 discloses the treatment of cancer by the oral administration of a dose of from 200 mg to 1 gram of gallium chloride per day for at least 2 months.
However, in spite of its established utility, the use of gallium in the treatment of such diseases is hampered by the fact that ionic gallium lacks high bioavailability when delivered orally. In fact, ionic gallium is a form of gallium which is poorly absorbed by the gastrointestinal tract. In this regard, Warrell et al..sup.4 disclose that when a composition of gallium nitrate is administered orally to a dog, only 0.5 to 2% of the gallium is absorbed from the gastrointestinal tract, into the bloodstream and then excreted into the urine. The percent absorption of other Ga.sup..3 salts is not likely to be significantly different, as such salts dissociate in aqueous solutions to produce mainly trivalent gallium ions in a similar manner to gallium nitrate.
The low bioavailability of orally delivered gallium salts (i.e., ionic gallium) and the need to generate blood plasma gallium concentrations in the patient of from 0.1 to 5 .mu.g/ml of plasma gallium concentration (and preferably 0.5 to 2 .mu.g/ml) for the treatment of hypercalcemia or excessive bone resorption.sup.5 requires that either impractically large doses of orally delivered gallium be administered to the patient or that the gallium be administered via non-oral means (e.g., intravenous delivery). The oral delivery of such gallium salts is not believed to be practical particularly with widespread, chronic conditions such as osteoporosis and the like.
The present invention is directed to the discovery that gallium bioavailability via oral administration is greatly enhanced by using electrostatically neutral gallium chelates of certain 3-hydroxy-4-pyrones. The present invention is directed to the further discoveries that because such neutral gallium chelates decompose in the acidic conditions commonly present in the stomach, pharmaceutical compositions of orally delivered neutral gallium chelates must contain means to inhibit dissociation of the neutral gallium chelates under such acidic conditions.
In regard to the above, it is noted that Finnegan et al..sup.15 disclose the preparation of aluminum and gallium complexes of some 3-hydroxy-4-pyrones, including maltol. This reference recites that the aluminum maltol complex is highly neurotoxic when injected intracranially into rabbits, and suggests further neurotoxicity experiments with the aluminum and gallium complexes. This reference further recites nuclear magnetic resonance spectroscopy (NMR) experiments that demonstrated significant differences between the aqueous behavior of the complexes of aluminum and gallium, i.e., experiments to determine the stability of gallium complexes as a function of pH could not be performed, whereas such experiments were readily performed on aluminum complexes.
Further regarding the significant differences between aluminum and gallium, aluminum is well known in the art to be a cause of degenerative bone diseases as well as being neurotoxic. Contrarily and as previously discussed, gallium is known in the art as effective in the treatment of degenerative bone disease and has shown no reported evidence of neurotoxicity.
Farrar et al..sup.16 discloses the preparation of an aqueous solution containing 10 mM maltol, 1 mM Ga(NO.sub.3).sub.3, and a trace of GaCl.sub.3 labelled with radioactive .sup.67 Ga for administration to rats by oral gavage. However, it is not established in this reference that this solution contains a significant amount of the neutral 3:1 complex. In any event, Farrar et al. completely fail to even consider the possibility that pH might affect the stability of a Ga-maltol complex. This reference also completely fails to realize, suggest, or imply any method to increase gallium absorption in fed animals. Additionally, this reference fails to suggest combining such gallium complexes with means to inhibit dissociation of the complex in a mammalian stomach.
Lastly, Hider et al..sup.14 disclose orally deliverable pharmaceutical compositions containing neutral iron complexes of 3-hydroxy-4-pyrones and means to inhibit dissociation of such complexes under acidic conditions. However, the teachings of this reference are expressly limited to iron and it is art recognized that gallium is not equivalent to iron. Further in this regard, iron is a Group VIII metal that is easily oxidized and reduced between its +2 and +3 valences at physiologic conditions, whereas gallium is a Group IIIa semi-metal that exists only with a +3 valence state at physiologic conditions.